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Molecular and Cellular Biology, January 2002, p. 221-230, Vol. 22, No. 1
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.1.221-230.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Characterization of U2AF⁶, a Splicing Factor Related to U2AF³⁵

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390,¹ Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030²

Received 22 June 2001/ Returned for modification 17 July 2001/ Accepted 5 October 2001

The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF⁶⁵) and 35-kDa (U2AF³⁵) subunits. U2AF³⁵ has multiple functions in pre-mRNA splicing. First, U2AF³⁵ has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF³⁵ is thought to play a role in the recruitment of U2AF⁶⁵ by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. It has been proposed that the physical interaction between the arginine-serine-rich (RS) domain of U2AF³⁵ and SR proteins is important for this activity. However, other data suggest that this may not be the case. Here, we report the identification of a mammalian gene that encodes a 26-kDa protein bearing strong sequence similarity to U2AF³⁵, designated U2AF²⁶. The N-terminal 187 amino acids of U2AF³⁵ and U2AF²⁶ are nearly identical. However, the C-terminal domain of U2AF²⁶ lacks many characteristics of the U2AF³⁵ RS domain and, therefore, might be incapable of interacting with SR proteins. We show that U2AF²⁶ can associate with U2AF⁶⁵ and can functionally substitute for U2AF³⁵ in both constitutive and enhancer-dependent splicing, demonstrating that the RS domain of the small U2AF subunit is not required for splicing enhancer function. Finally, we show that U2AF²⁶ functions by enhancing the binding of U2AF⁶⁵ to weak 3' splice sites. These studies identify U2AF²⁶ as a mammalian splicing factor and demonstrate that distinct U2AF complexes can participate in pre-mRNA splicing. Based on its sequence and functional similarity to U2AF³⁵, U2AF²⁶ may play a role in regulating alternative splicing.

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